Faculty Collaboration Database

Tumor Derived Extracellular Vesicles Drive T Cell Exhaustion in Tumor Microenvironment through Sphingosine Mediated Signaling and Impacting Immunotherapy Outcomes in Ovarian Cancer. Adv Sci (Weinh) 2022 May;9(14):e2104452

Date

03/16/2022

Pubmed ID

35289120

Pubmed Central ID

PMC9108620

DOI

10.1002/advs.202104452

Scopus ID

2-s2.0-85126251446 (requires institutional sign-in at Scopus site)   36 Citations

Abstract

SPHK1 (sphingosine kinase-1) catalyzes the phosphorylation of sphingosine to sphingosine-1-phosphate (S1P), is found to be highly expressed in solid tumors. Here, extracellular vesicles (EVs) are identified as the key transporters of SPHK1 to the tumor microenvironment. Consequently, SPHK1-packaged EVs elevate S1P levels in the tumor microenvironment, where S1P appears as an immunosuppressive agent. However, the exact mechanism of how S1P mediates its immunosuppressive effects in cancer is not understood. It is investigated that S1P can induce T cell exhaustion. S1P can also upregulate programmed death ligand-1 (PDL-1) expression through E2F1-mediated transcription. Notably, an SPHK1 inhibitor PF543 improves T cell-mediated cytotoxicity. Furthermore, combining PF543 with an anti-PD-1 antibody reduces tumor burden and metastasis more effectively than PF543 alone in vivo. These data demonstrate a previously unrecognized mechanism of how SPHK1-packaged EVs contribute to the progression of ovarian cancer and thus present the potential clinical application of inhibiting SPHK1/S1P signaling to improve immune checkpoint blockage (anti-PD-1 antibody) therapy in ovarian cancer.

Author List

Gupta P, Kadamberi IP, Mittal S, Tsaih SW, George J, Kumar S, Vijayan DK, Geethadevi A, Parashar D, Topchyan P, McAlarnen L, Volkman BF, Cui W, Zhang KYJ, Di Vizio D, Chaluvally-Raghavan P, Pradeep S

Authors

Pradeep Chaluvally-Raghavan PhD Associate Professor in the Obstetrics and Gynecology department at Medical College of Wisconsin
Anjali Geethadevi PHD Research Scientist I in the Obstetrics and Gynecology department at Medical College of Wisconsin
Lindsey A. McAlarnen MD Gynecology Oncology Fellow in the Obstetrics and Gynecology department at Medical College of Wisconsin
Deepak Parashar PhD Assistant Professor in the Medicine department at Medical College of Wisconsin
Sunila Pradeep PhD Associate Professor in the Obstetrics and Gynecology department at Medical College of Wisconsin
Shirng-Wern Tsaih Research Scientist II in the Obstetrics and Gynecology department at Medical College of Wisconsin
Brian F. Volkman PhD Professor in the Biochemistry department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Extracellular Vesicles
Female
Humans
Immunotherapy
Ovarian Neoplasms
Receptors, Lysosphingolipid
Sphingosine
T-Lymphocytes
Tumor Microenvironment